Aldehyde Dehydrogenase Inhibitors: a further challenge in the fight against cancer

Members of aldehyde dehydrogenase 1A family are commonly acknowledged as hallmarks of cancer stem cells and their overexpression is significantly associated with poor prognosis in different types of malignancies. Accordingly, treatments targeting these enzymes may represent a successful strategy to fight cancer. Here we present a novel series of imidazol[1,2-a]pyridines, designed as aldehyde dehydrogenase inhibitors by means of a structured-based optimizations of a previously developed lead, GA11 [1]. The novel compounds were evaluated in vitro for their activity and selectivity against the three isoforms of the ALDH1A family, and investigated through crystallization and modeling studies for their ability to interact the catalytic site of the 1A3 isoform. Tested in vitro on different populations of CSCs, including glioma and prostate cancer stem cells, representative imidazo[1,2-a]pyridine derivatives displayed also a relevant anti-proliferative efficacy. Results obtained will be discussed